BACKGROUND: The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching. METHODS: A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results. RESULTS: We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing. CONCLUSIONS: Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.
BACKGROUND: The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching. METHODS: A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results. RESULTS: We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing. CONCLUSIONS: Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.
Authors: Ming Li; Andrew E Jaffe; Richard E Straub; Ran Tao; Joo Heon Shin; Yanhong Wang; Qiang Chen; Chao Li; Yankai Jia; Kazutaka Ohi; Brady J Maher; Nicholas J Brandon; Alan Cross; Joshua G Chenoweth; Daniel J Hoeppner; Huijun Wei; Thomas M Hyde; Ronald McKay; Joel E Kleinman; Daniel R Weinberger Journal: Nat Med Date: 2016-05-09 Impact factor: 53.440
Authors: X Chen; G Lee; B S Maher; A H Fanous; J Chen; Z Zhao; A Guo; E van den Oord; P F Sullivan; J Shi; D F Levinson; P V Gejman; A Sanders; J Duan; M J Owen; N J Craddock; M C O'Donovan; J Blackman; D Lewis; G K Kirov; W Qin; S Schwab; D Wildenauer; K Chowdari; V Nimgaonkar; R E Straub; D R Weinberger; F A O'Neill; D Walsh; M Bronstein; A Darvasi; T Lencz; A K Malhotra; D Rujescu; I Giegling; T Werge; T Hansen; A Ingason; M M Nöethen; M Rietschel; S Cichon; S Djurovic; O A Andreassen; R M Cantor; R Ophoff; A Corvin; D W Morris; M Gill; C N Pato; M T Pato; A Macedo; H M D Gurling; A McQuillin; J Pimm; C Hultman; P Lichtenstein; P Sklar; S M Purcell; E Scolnick; D St Clair; D H R Blackwood; K S Kendler Journal: Mol Psychiatry Date: 2010-09-14 Impact factor: 15.992
Authors: Verónica T Cheli; Richard W Daniels; Ruth Godoy; Diego J Hoyle; Vasundhara Kandachar; Marta Starcevic; Julian A Martinez-Agosto; Stephen Poole; Aaron DiAntonio; Vett K Lloyd; Henry C Chang; David E Krantz; Esteban C Dell'Angelica Journal: Hum Mol Genet Date: 2009-12-16 Impact factor: 6.150
Authors: C A Ghiani; M Starcevic; I A Rodriguez-Fernandez; R Nazarian; V T Cheli; L N Chan; J S Malvar; J de Vellis; C Sabatti; E C Dell'Angelica Journal: Mol Psychiatry Date: 2009-06-23 Impact factor: 15.992